PHASES OF CLINICAL TRIALS

What is Clinical Trial ??

“A systematic study of pharmaceutical products

on human subjects (whether patients or non
patients volunteers) in order to verify;
▪ Clinical, pharmacological (including
pharmacodynamics and pharmacokinetics) and
▪ adverse effects, with the objective of determining
their safety and efficacy”
2
3
 Why Are Clinical Trials Important?

✓ Does the new treatment work in humans?

✓ Is the new treatment safe?

Clinical trials,
➢ Answer critical research questions
➢ Find better treatments and ways to prevent disease

Translate results of basic scientific research into better ways to

prevent, diagnose, or treat disease.
4
Phase O
Micro-dosing studies
 Phase 0 trials are also known as human
micro dosing studies and are designed to
speed up the development of promising
drugs by establishing very early on
whether the drug or agent behaves in
human subjects as was expected
from preclinical studies.
Phase O (Micro-dosing studies)
❖ New viable tool in drug development toolbox

❖ By definition, FDA –

“Use of 100 mcg of candidate drug or less than 1/100th of the

pharmacological dose determined from the animal models and in
vitro systems using the test substance”

FDA further adds – “a maximum micro dose of <30 nanomoles of

protein product”

❖ Small sample size of 10 -15 subjects is required

6
Why conduct micro dose studies ??
❖To obtain information on human pharmacokinetics as
early as possible.

❖Compare ADME parameters for several drug candidates

where animal data may be conflicting.

❖Helps in selecting the first dose for a Phase I study

7
Goal of Phase 0 studies

❖ To assess whether the mechanism of action

defined in pre clinical studies is achieved or not

❖ Determine special methods to assess the

pharmacokinetics of the drug.

❖ Develop novel models to evaluate the

pharmacodynamics
 Advantages Of Micro dosing

❖Requires minute quantities of drug – not intended to

produce any pharmacological effect; risk of adverse
events less.

❖Decreases time of drug development

❖Helps patients and industry with earlier availability

of test drugs.

9
 Limitations Of Micro Dosing

body’s reaction to
❖ Insufficient information on
micro dose and pharmacological dose.

❖ Micro dosing may not be predict kinetic

parameters accurately for drugs showing
non-linear kinetics.

❖ Metabolism and stability of compounds.

Phase I:
Human Pharmacology Studies

➢ Done in small group of 20 -80 healthy volunteers

➢ Includes trials designed to assess the safety,
pharmacokinetics and pharmacodynamics of a
drug.
➢ Some of the Phase I trials include,
 Single Ascending dose studies
 Multiple Ascending dose studies

 - Pharmacogenomics studies (PGx)

Single Ascending dose Multiple Ascending dose
studies
• Small group of subjects given • A group of subjects receives

single dose of drug and multiple low doses of the drug

observed for a period of time. • Samples (of blood and other

• If Pk data is in line with body fluids) collected at various

predicted safe values, the dose time points and analysed

is increased in a new group of • Gives better understanding of

subjects pharmacokinetics and

• Continued till maximum
pharmacodynamics of the drug
tolerated dose (MTD) is defined.
Pharmacogenomics Study
✓ Broadly refers to the study of drug exposure
and/or response as related to variations in DNA
and RNA characteristics and Contribute to a
greater understanding of inter-individual
differences in the efficacy and safety of
investigational drugs.
Phase 1 studies
Objectives:
✓ To assess the absorption, distribution,
routes and rates of excretion
✓ To assess the metabolite profile and
metabolite

14
 Information Obtained From
Phase I Studies

❖ Maximum tolerated dose

❖ Nature of adverse reactions that can be expected

❖ Preliminary characterization of the drug

❖ Accumulation of parent drug/ metabolites

❖ Bioavailability in presence of food

15
Phase I/II (Phase I in patients)

❖ Test drug is too toxic to be tested in healthy volunteers

E.g. anticancer drugs, HIV

❖ Therapeutic range/ratio is too narrow to test E.g.

Antiarrhythmic

❖ Dose in patient > Normal Volunteers can tolerate E.g.

Neuroleptics

16
Phase IIa ; Therapeutic Exploratory
Studies
 Objectives:

✓ Study therapeutic effect.

✓ Confirm the hypothesis

conceptualized.
Features
❖ Treatment against disorder.
❖ Homogenous population.
❖ Strict inclusion and exclusion criteria.
❖ Placebos and fixed treatment regimens
❖ One or more than one dose tested
❖ Long washout” period is required between
treatments.
Phase IIa studies
 Sample size:50 – 500 subjects
❖ Clinical parameters: Symptoms and sign of
disease
❖ Laboratory tests: measure or study disease
❖ Biomarkers: include biochemical
markers for disease prognosis.
❖ PK analysis.
 Information obtained from
Phase IIa studies

❖Proves primary hypothesis

❖ Efficacy

❖Effect Size

❖Adverse events (ADR of special interest)

20
Phase IIb – Dose Range Finding
 Objectives:
✓ Determine optimal dose-response range
 Features:
❖ Test different doses and find optimal dose

❖ Patient population defined

❖ Placebo/Active controlled criteria

❖ Tight inclusion and exclusion criteria

Phase IIb – Dose range finding
 Sample size: 300 – 400 subjects

❖ Clinical parameters

❖ Laboratory tests (centralized)

❖ PK and Population PK

 Endpoints
 Clinical Endpoint (preferred)
 Information obtained from
Phase IIb studies
❖ Dose-response

❖ Frequency

❖ Additional ADR

❖ Type of patients more responsive to treatment.

20
Phase IIIa (Confirmatory trials)
 Objectives:
❖ To confirm safety and effectiveness of the drug
❖ Basis for marketing approval (NDA application)
Features:
❖ Active controlled studies
❖Conducted in patients in whom the drug will be
eventually intended. E.g. Mild Asthmatics,
Moderate and severe Diarrhea.
❖ Inclusion and exclusion criteria relatively relaxed
❖ Different dosages and combinations with other
drugs
❖ Different patient population
❖ Multi-center / Multinational trial
Phase IIIa – Confirmatory Trials
 Sample size:
 Several hundred to around 3000 patients

 Efficacy Targets:
❖ Clinical parameters
❖ Laboratory tests
❖ Diagnostic test

 Endpoints:
 Clinical endpoint
 Information obtained from
Phase IIIa studies

❖Definitive proof of efficacy

❖Additional safety data in large patients

❖Adverse effects with longer duration of treatment

❖Information for package insert and labelling of

medicine.

27
Phase IIIb – Confirmatory Trials
Objectives:

Further explore dose-response relationship in different stages of

the disease and in combination with another drug

Features:

❖Clinical trial after regulatory submission of an NDA but

prior to approval and launch

❖ Supplement earlier trials, complete earlier trials, directs

towards new trials or phase IV evaluations

28
 Post Marketing Studies
 Types:
✓ Phase IV studies
✓ Post marketing Surveillance (PMS)

Objectives:
❖ Regulators gather additional information about
a products safety efficacy, or optimal use.
❖ Agreed with regulators at the time of approval
of drug.
Phase IV studies
 Features
❖ Real life scenario
❖ Inclusion/exclusion criteria are not stringent, wider
patient population.
❖ Competitive reason of finding new market for drug.
❖ Interaction with other drug if not tested earlier
❖ Special population groups such as pregnant
women.
❖ Study long term side effect.
Post Marketing Surveillance
Features:
❖ Part of pharmacovigilance plan. (Risk Management Plan-RMP)
❖ Rare adverse effects E.g. Immunogenicity.
❖ Long Term adverse effects on larger population for longer
period.
❖ Monitor safety by
✓ Spontaneous reporting databases
✓ Prescription event monitoring
✓ Electronic health records
✓ Patient registries and records
✓ Surveillance minimises harmful consequences and
maximise optimal use of drug.

31
 Phase I Phase II Phase III Phase IV
First in First in Multi-Site Post Marketing
Human Patient Trial Surveillance

10-100 participants 50-500 participants A few hundred Many thousands

thousand to a few of participants
thousand participants
Usually healthy Patient-subject receiving Patient-subject receiving Patients in treatment with
volunteers;
occasionally patients with experimental drug experimental drug approved drug
advanced or rare disease.

Open Label Randomized & Randomized and Open label

controlled (can be controlled (can be
placebo- placebo-controlled;
controlled):may be may be blinded
blinded
Safety and tolerability Efficacy and dose Confirm efficacy in larger Adverse events compianlce,
ranging population drug-drug interactions

Months to 1 year 1-2 years 3-5 years No fixed duration

U.S. $10million U.S. $20million U.S. $50-100 million

Success rate: 50% Success rate: 30% Success rate: 25-50%

Human Pharmacology Therapeutic Exploratory Therapeutic Confirmatory Therapeutic Use 31